Previously, peptidomimetic class II MHC blockers were designed by modifying the sequence of antigenic peptides which associate with MHC proteins. A drawback of this approach is that such modifications are highly specific to a particular class II MHC protein, and cannot be applied for designing blockers against other MHC molecules. Here, we demonstrate a novel approach of designing MHC blockers through structural modification of antigenic peptide. By synthesizing a library of antigenic peptide analogues with varying degrees of Polyproline II (PPII) conformations, we demonstrate that some of these structurally modified analogues display higher binding affinity to HLA DQ2 and also display superior suppression of proliferation of two celiac disease associated T cell lines. As it was previously reported that antigenic peptides bound to most of the class II MHC molecules adopt a common PPII helical secondary structure, the strategy of developing MHC blockers this strategy may be applied to develop blockers against multiple class II MHC molecules